Mutant FOXO1 Controls an Oncogenic Network via Enhancer Accessibility and RNA Polymerase Pause Release [RNA-Seq]

Transcriptional dysregulation is a hallmark of diffuse large B-cell lymphoma (DLBCL), as multiple transcriptional regulators are mutated. However, our mechanistic understanding of how normal transcriptional programs are co-opted in DLBCL has been hindered by a lack of methodologies that provide the temporal resolution required to separate direct and indirect effects in transcriptional control. Here, we applied a chemical-genetic approach to engineer the inducible degradation of the transcription factor FOXO1, which is recurrently mutated in DLBCL. The combination of rapid degradation of FOXO1, nascent transcript detection, and accessible chromatin allowed us to identify the direct targets of FOXO1. FOXO1 degradation impaired RNA polymerase pause-release at many target genes. Furthermore, FOXO1 was required to maintain accessibility at specific enhancers associated with target genes. Importantly, many direct targets of FOXO1 were oncogenes including several effectors of the PI3K pathway, which creates a dependency on AKT signaling.